The TGF-β protein family consists of three distinct isoforms (TGF-β1, -β2, and -β3) whose pathways activate and regulate multiple gene responses that influence disease states such as, e.g., cell proliferative, inflammatory, and cardiovascular conditions. TGF-β isoform expression in cancer is complex and variable with different combinations of TGF-β isoforms having different roles in particular cancers. For example, TGF-β1 and -β3 play a greater role in ovarian cancer and its progression than TGF-β2; while TGF-β1 and -β2 expression is greater in higher grade chondrosarcoma tumors than -β3. In human breast cancer, TGF-β1 and -β3 are highly expressed, with -β3 expression correlating with overall survival—patients with node metastasis and positive TGF-β3 expression have poor prognostic outcomes. However, in colon cancer, TGF-β1 and -β2 are more highly expressed than -β3 and are present at greater circulating levels than in cancer-free individuals. In glioma cancer, TGF-β2 is pivotal for cell migration. Consequently, there is a need to modulate multiple TGF-β isoform expression in cell proliferation conditions such as cancer.
U.S. Pat. No. 5,571,714 discloses the use of anti-TGF antibodies in treating malignancies and metastatic cancer, and in particular, discloses a murine antibody designated 1D11.16 (ATCC No. HB9849) that is said to bind both TGF-β1 and -β2. This document states that antibody 1D11.16 binds TGF-β2 with a Ka of merely 3.4×108 L/mol (Kd=1/Ka).
The treatment of cell proliferative disorders, such as malignancies and cancers, may be improved by use of antibodies that neutralize mature, human, TGF-β1, -β2, and -β3 with improved binding kinetics and affinity. Substantial physical and chemical stability, adequate pharmacokinetics, and good solubility are also desirable for a pharmaceutical product. Consequently, an unmet need remains for antibodies having characteristics suitable for the pharmaceutical treatment of cell proliferative disorders.